Bicycloheptyl, aralkyl-ureas



United States Patent 3,115,524 BICYCLOHEPTYL, ARALKYL-UREAS Seymour L. Shapiro, Hastings on Hudson, and Louis Freedman, Bronxvilie, N.Y., assignors to US. Vitamin ice of high potency, and serve as intermediates as Well for the preparation of the ureas of the formula shown:

& Pharmaceutical Corporation, New York, N.Y., a cor- 5 poration of Delaware No Drawing. Filed Mar. 15, 1961, Ser. No. 95,833

2 Claims. (Cl. 260--553) These ureas, in turn, are useful pharmacological agents and show particular eiiectiveness as anti-inflammatory This invention is concerned with novel secondary agents and muscle relaxants. amines derived by the alkylation of (2,5-endomethyl- In the practice of this invention, the (2,5-endomethylene)-cyclohexylmethylamine and in particular the sece-ne)-cyciohexylmethylamine is treated in aqueous acetoondary amines of the following structure: nitrile with ar-alkyl halide or cycloalkyl alkyl halide, using sodium hydroxide as an acid scavenger, following the H procedure described by Shapiro et al., J. Am. Chem. Soc.

I 81,3728 (1959). I\OH2N R1 In addition to the secondary amine, quantities of the a tertiary amine of the structure:

OHzi R1 I [i wherein R is a cycloalkylalkyl radical or aralkyl radical having a carbon content of C -C and embodies as well are b i i haloaralkyl radicals and polyhaloaralkyl radicals Such as compcunds of invention are hown in the fOT example o-chlorobenzyl, 3,4-dlchlorobfilllyli P- table, wherein R is introduced to distinguish between the chloro-p-phenethyl and the llke. classes of compounds involved, i.e., R H gives the sec- The secondary amines of this invention have theraondary amine, RFR gives the tertiary amine, and peutic utility per se, particularly as local anesthetic agents R =CONH gives the urea.

TABLE Ilia orn-NR1 r Analyses, percent M.P. =0 (Rs) R1 or 13.1 (mm. Formula Carbon Hydrogen Nitrogen press.)

02.10. Found Cale. Found Cale. Found Rz=l1ydrogen 0.111 011? 116-120(0. 5) CfiHnN 33.7 83.6 9.3 10.5 6.5 0.3 -136(04) o rimomfi 7 .1 72.2 8.1 8.8 5.6 5.7 148-152(0. 5) C15H20C1N .6 6.0

260265 (A) cml'lzoClgN 94-98(0. 15) 01 mm"..- 289-290 (B CIEIIHBI'NH 136-142(05) 10H2aN 285-290 mH 4BIN.. 120-122 (0. 1) mHggN 166-170 (0. 5) 4. 6 4. 6 192-196 (0. 5) 3. 7 3. 0 204-210 (0. 5) 3. 7 3. 7 90-9103 3.1 3.1 230-238(0. 05) 3.1 3.1 170-1760) 1) 4.2 4.3 184-186(0. 5) 4. 2 4. 0 O H,,0H2OH -198(0. 1) 4.1 3.7

R OONH O H OHF 102-104(0) CMHQQNQO 74.4 74.4 8.6 8.2 10.8 10.8 p-ClCgH4OHz 146-148(D) CmHnClNzO 65.7 65.7 7.2 6.5 9.6 9.6 0611 011 01121 77-79(D) C17II24N20... 75.0 75.3 8.9 9.1 CoHnCHzCHr- 106-108(0) CnHaoNzO 110.1 10.3

e. e Hydrochloride of indicated base. d Hydrobromide of preceding compound.

' CBH|1CHQCH2- is cyelohexylethyl.

The secondary amines of this invention form salts with the strong mineral acids such as for example hydrobromides and hydrochlorides and in their employment as pharmacological agents, this is the preferred form for these compounds.

The ureas of this invention are sparingly soluble in water although they show oral activity upon administration in pharmacological testing, indicating that they are absorbed on administration through this route.

As illustrative of the practice of this invention, the following examples are given, which are not to be considered as limiting.

Example 1 N- o-CHLOROBENZYL) 2, 5-ENDOMETHYLENE) -CYCLO- I-IEXYL-METHYLAMINE A mixture of 25 g. (0.2 mole) of (2,5-endomethylene)-cyclohexylmethylamine in 47 ml. of water, ml. of 40% soduim hydroxide and 34 ml. of acetonitrile, was treated with 32.2 g. (0.2 mole) of o-chlorobenzyl chloride in 26 ml. of acetonitrile. The reaction mixture was securely stoppered, shaken intermittently during a storage period of 72 hours at 20 and then decanted into 660 ml. of water. The formed oil was separated, dissolved in ether, dried (anhydrous magnesium sulfate), the ether evaporated, and the product distilled. Upon fractional distillation, the product was obtained at 130136 at 0.4 mm. whereas the tertiary amine reflecting addition of 2- o-chlorobenzyl groups was obtained as a fraction, boiling at 192-196" at 0.5 mm.

In a similar fashion the other secondary amines de scribed in the table were obtained along with the corresponding tertiary amines, upon substituting the appropriate halide and their properties have been noted in the table above. The secondary amines on treatment with an equivalent of hydrochloric acid or hydrobromic acid afford the corresponding hyd-rohalide salt.

EXAMPLE 2 N1- (2,5-ENDOMETHYLENE -CYCLO HEXYLMETHYL, N -p-CHLOROBENZYL UREA A mixture of 3 g. (0.012 mole) of N-p-chlorobenzyl- (2,5-endomethylene)-cyclohexylmethylamine and 2 g. of

nitrourea in 15 ml. of ethanol was heated on the steam bath with noted evolution of gas. ethanol was removed, and the oily residue on treatment with 15 ml. of ethanol followed by 5 ml. of water precipitated the product, 4.1 g., melting point which was recrystallized (acetonitrile) to give 2.3 g. of pure product, melting point 146-148".

In a similar manner the secondary amines shown in the table above are converted to the corresponding ureas and typical other examples have been characterized in the table.

It is to be understood that it is intended to cover all changes and modifications of the examples of the invention herein chosen for the purpose of illustration which do not constitute departures from the spirit and scope of the invention.

We claim:

1. The compound of the formula wherein R is selected irom the group consisting of phenyl-lower alkyl and chlorophenyl-lower alkyl, wherein the lower alkyl has from 1 to 3 carbon atoms.

2. The compound of claim 1, wherein R is p-chlorobenzyl.

References Cited in the file of this patent UNITED STATES PATENTS 1,785,730 Davis Dec. 23, 1930 2,673,877 Thompson Mar. 30, 1954 2,831,027 Pfister Apr. 15, 1958 2,838,568 Brust June 10, 1958 FOREIGN PATENTS 1,081,453 Germany May 12, 1960 497,042 Great Britain June 13, 1938 573,509 Great Britain Aug. 17, 1944 OTHER REFERENCES Fieser: Organic Chemistry (1956), pages 46-47.

After one hour the 

1. THE COMPOUND OF THE FORMULA 